Abstract
Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function—nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity—appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals.
Footnotes
↵1 The authors declare no competing financial interests.
↵3 This work was supported by the Research Grants Counsel of Hong Kong (Grants GRF660813, HKSAR and HKUST12/CRF/13G), the National Institutes of Health (Grants NS70193), and the National Key Basic Research Program of China (2013CB530900) to K.H. Support was also received from the University of Pittsburgh Alzheimer’s Disease Research Center Brain Bank (Grant P50 AG005133), the Washington University in St. Louis Alzheimer’s Disease Research Center (Grant P50 AG05681), and the BrightFocus Foundation (Grants 100006312 and A2012101).
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